Acidic Microenvironment Enhances Cisplatin Resistance in Bladder Cancer via Bcl-2 and XIAP
Cisplatin (CDDP) remains a key drug for patients with advanced bladder cancer (BC), despite the emergence of new therapeutic agents; thus, the identification of factors contributing to CDDP treatment resistance is crucial. As acidity of the tumor microenvironment has been reported to be associated w...
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2025-01-01
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| author | Kaede Hiruma Vladimir Bilim Akira Kazama Yuko Shirono Masaki Murata Yoshihiko Tomita |
| author_facet | Kaede Hiruma Vladimir Bilim Akira Kazama Yuko Shirono Masaki Murata Yoshihiko Tomita |
| author_sort | Kaede Hiruma |
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| description | Cisplatin (CDDP) remains a key drug for patients with advanced bladder cancer (BC), despite the emergence of new therapeutic agents; thus, the identification of factors contributing to CDDP treatment resistance is crucial. As acidity of the tumor microenvironment has been reported to be associated with treatment resistance and poor prognosis across various cancer types, our objectives in this study were to investigate the effects of an acidic environment on BC cells and elucidate the mechanisms behind CDDP resistance. Our findings show that BC cells cultured under acidic conditions developed cisplatin resistance as acidity increased. Notably, CDDP administered to BC cells in a pH 6.0 environment required double the concentration, compared to those in a pH 7.5 environment, to achieve equivalent toxicity. Using chloroquine and navitoclax, we identified the involvement of the Bcl-2 and LC3B pathways in the acquisition of CDDP resistance under acidic conditions. A Western blot analysis revealed that the activations of Bcl-2 and XIAP expression appear to inhibit both apoptotic and autophagic cell death. Taken together, these results suggest that alleviating the acidity of the tumor microenvironment in clinical settings might enhance BC sensitivity to CDDP. |
| format | Article |
| id | doaj-art-a671909900e2419ea08e8291bf687947 |
| institution | Kabale University |
| issn | 1467-3037 1467-3045 |
| language | English |
| publishDate | 2025-01-01 |
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| spelling | doaj-art-a671909900e2419ea08e8291bf6879472025-01-24T13:27:30ZengMDPI AGCurrent Issues in Molecular Biology1467-30371467-30452025-01-014714310.3390/cimb47010043Acidic Microenvironment Enhances Cisplatin Resistance in Bladder Cancer via Bcl-2 and XIAPKaede Hiruma0Vladimir Bilim1Akira Kazama2Yuko Shirono3Masaki Murata4Yoshihiko Tomita5Department of Urology, Division of Molecular Oncology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, JapanDepartment of Urology, Division of Molecular Oncology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, JapanDepartment of Urology, Division of Molecular Oncology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, JapanDepartment of Urology, Division of Molecular Oncology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, JapanDepartment of Urology, Division of Molecular Oncology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, JapanDepartment of Urology, Division of Molecular Oncology, Graduate School of Medical and Dental Sciences, Niigata University, Niigata 951-8510, JapanCisplatin (CDDP) remains a key drug for patients with advanced bladder cancer (BC), despite the emergence of new therapeutic agents; thus, the identification of factors contributing to CDDP treatment resistance is crucial. As acidity of the tumor microenvironment has been reported to be associated with treatment resistance and poor prognosis across various cancer types, our objectives in this study were to investigate the effects of an acidic environment on BC cells and elucidate the mechanisms behind CDDP resistance. Our findings show that BC cells cultured under acidic conditions developed cisplatin resistance as acidity increased. Notably, CDDP administered to BC cells in a pH 6.0 environment required double the concentration, compared to those in a pH 7.5 environment, to achieve equivalent toxicity. Using chloroquine and navitoclax, we identified the involvement of the Bcl-2 and LC3B pathways in the acquisition of CDDP resistance under acidic conditions. A Western blot analysis revealed that the activations of Bcl-2 and XIAP expression appear to inhibit both apoptotic and autophagic cell death. Taken together, these results suggest that alleviating the acidity of the tumor microenvironment in clinical settings might enhance BC sensitivity to CDDP.https://www.mdpi.com/1467-3045/47/1/43potential hydrogen (pH)aciditybladder cancercisplatinBcl-2XIAP |
| spellingShingle | Kaede Hiruma Vladimir Bilim Akira Kazama Yuko Shirono Masaki Murata Yoshihiko Tomita Acidic Microenvironment Enhances Cisplatin Resistance in Bladder Cancer via Bcl-2 and XIAP Current Issues in Molecular Biology potential hydrogen (pH) acidity bladder cancer cisplatin Bcl-2 XIAP |
| title | Acidic Microenvironment Enhances Cisplatin Resistance in Bladder Cancer via Bcl-2 and XIAP |
| title_full | Acidic Microenvironment Enhances Cisplatin Resistance in Bladder Cancer via Bcl-2 and XIAP |
| title_fullStr | Acidic Microenvironment Enhances Cisplatin Resistance in Bladder Cancer via Bcl-2 and XIAP |
| title_full_unstemmed | Acidic Microenvironment Enhances Cisplatin Resistance in Bladder Cancer via Bcl-2 and XIAP |
| title_short | Acidic Microenvironment Enhances Cisplatin Resistance in Bladder Cancer via Bcl-2 and XIAP |
| title_sort | acidic microenvironment enhances cisplatin resistance in bladder cancer via bcl 2 and xiap |
| topic | potential hydrogen (pH) acidity bladder cancer cisplatin Bcl-2 XIAP |
| url | https://www.mdpi.com/1467-3045/47/1/43 |
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